Carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl ester (hereinafter also referred to as “carbamate compound”) is useful in the treatment of CNS disorders, particularly anxiety, depression, convulsions, epilepsy, migraine, manic depression, drug abuse, smoking, attention deficit hyperactivity disorder (ADHD), obesity, sleep disorders, neuropathic pain, stroke, cognitive impairment, neurodegeneration, muscle spasm due to stroke and the like, according to its anticonvulsant effects.
The carbamate compound is prepared from a compound of Formula 1a, which is obtained from a substitution reaction of a compound of Formula 2 and a compound of Formula 3, as an intermediate. Conventionally, a base is added to the compound of Formula 2, and a tetrazole solution is then added thereto to carry out a substitution reaction. However, in this case, the compound of Formula 1b, which is a positional isomer thereof, in addition to the desired compound of Formula 1a, is obtained together as a mixture by the substitution reaction (WO 2011/046380).




(In the Formulas, R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, perfluoroalkyl having 1 to 8 carbon atoms, alkyl having 1 to 8 carbon atoms, thioalkoxy having 1 to 8 carbon atoms and alkoxy having 1 to 8 carbon atoms; and X is a leaving group)
Furthermore, when the compound of Formula 2 and the compound of Formula 3 are subjected to the substitution reaction, the reaction selectivity of number 1 nitrogen of the compound of Formula 3 is better than the reaction selectivity of number 2 nitrogen, and thus the compound of Formula 1b is produced with superior selectivity with respect to the compound of Formula 1a (Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), (7), 1157-63; 1986). Therefore, according to the conventional method, the compound of Formula 1a used for preparing the carbamate compound is less produced than the compound of Formula 1b, and thus the yield is low when preparing the carbamate compound by using the compound of Formula 2 and the compound of Formula 3 as starting materials.
In this regard, there is an alternative method for selectively preparing only a compound of the same form as substituted with number 2 nitrogen by synthesizing a tetrazole ring shape (Chem. Pharm. Bull. 30(9) 3450-3452; 1982). However, there may be problems in that it is difficult to be commercially used since a diazomethane-based material—which has a risk of explosion during the reaction—is used, and 2 equivalents or more of lithium diisopropylamide is used as a raw material.
As such, there is a need for developing a method that the aryl 2-tetrazol-2-yl ketone of Formula 1a may be prepared from the compound of Formula 2 and the compound of Formula 3 with better selectivity than the aryl 2-tetrazol-1-yl ketone of Formula 1b, and as a result, can be commercialized while obtaining the aryl 2-tetrazol-2-yl ketone of Formula 1a and the carbamate compound in high yield.